Project Summary Sepsis, a systemic inflammatory response syndrome, is a life-threatening disease with high morbidity and mortality. Sepsis is often triggered by bacterial infection. Excessive inflammatory responses lead to vascular injury in sepsis including increased vascular permeability and edema. Identifying novel therapeutic targets that can help control sepsis-induced vascular injury is crucial to treat this devastating disease. Endothelial barrier dysfunction contributes to the pathogenesis of multi-organ failure in sepsis. Acetylation and deacetylation of cell-cell junction and cytoskeleton proteins may serve as an important mechanism to control the dynamics of endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate non-nuclear protein function through deacetylation. ?-catenin is an endogenous substrate for HDAC6. ?-catenin is a key component of adherens junction complex. ?-catenin interacts with VE-Cadherin at cell-cell junctions to maintain endothelial barrier integrity. In this project, we will investigate HDAC6 regulation of ?-catenin and endothelial adherens junctions in sepsis. In our preliminary studies, we demonstrated that HDAC6 knockdown or selective HDAC6 inhibition prevented TNF-? induced endothelial cell barrier disruption and increased ?-catenin acetylation in endothelial cells, which was associated with increased membrane localization of ?-catenin and stabilization of adherens junctions. Furthermore, in a mouse model of polymicrobial sepsis, HDAC6 inhibition was able to prevent sepsis-induced deacetylation of ?-catenin in lung tissues, which was associated with the protection of adherens junctions and reduced pulmonary edema. In the proposed studies, we will investigate molecular mechanisms of HDAC6 regulation of endothelial adherens junctions in sepsis using inducible endothelial-specific HDAC6 knockout mice. We will also assess the therapeutic potential of novel HDAC6 inhibitors in the protection of endothelial adherens junctions during sepsis.